Battling limitations

Despite advances in atypical antipsychotics, schizophrenia is still an area of unmet need, that affects approximately 1 per cent of the general population

Schizophrenia is a chronic psychiatric disorder that affects approximately 1 per cent of the general population. The symptoms of schizophrenia are generally classed as either negative or positive, but patients will often present with varying combinations of the two types.

Negative symptoms represent deficits in function, such as affective flattening, avolition and anhedonia, while positive symptoms are indicative of excess or distorted function, presenting as delusions, hallucinations and a racing, or incoherent style of speech.

The dopamine hypothesis of schizo-phrenia pathogenesis argues that the behavioural changes seen in patients are caused by excessive dopamine activity in certain regions of the brain, primarily the mesolimbic and mesocortical pathways.

Days gone by In the past, schizophrenia was treated with so-called typical antipsychotics, such as haloperidol, chlorpromazine and fluphenazine. These drugs are primarily dopamine receptor antagonists, effective in the treatment of positive symptoms.

However, their efficacy generally does not extend to the negative symptoms that are significantly correlated with long-term treatment outcomes.

Typical antipsychotics are also associated with a poor tolerability profile, causing notable movement disorders such as akathisia and tardive dyskinesia. These extrapyramidal adverse events frequently lead to poor patient compliance, another predictor of poor treatment response.

More recently, atypical antipsychotics including risperidone, quetiapine and olanzapine have played a major role in schizophrenia treatment. These drugs are generally dual-action serotonin and dopamine receptor antagonists and are more effective than the older typicals in addressing the positive symptoms as well as less likely to result in extrapyramidal adverse events.

Yet, despite the progress made with the introduction of the atypical agents, the condition still remains an area of unmet therapeutic need due to limited efficacy and a high incidence of adverse events.

Joint ventures Solvay and Lundbeck are developing bifeprunox (DU 127090), a partial dopamine D2 receptor antagonist that also has agonist effects at serotonin 1areceptors. Partial D2 antagonism is postulated to decrease dopaminergic activity in regions of the brain where it is excessive, while simultaneously increasing activity in hypoactive regions, thus acting as a dopaminergic stabiliser.

In preclinical studies, bifeprunox has demonstrated antipsychotic efficacy in schizophrenia animal models and results of phase III clinical trials have indicated that the drug is effective in treating both the negative and positive symptoms.

This novel agent also appears to have an encouraging tolerability profile as it is not associated with cardiotoxicity or weight gain, and neither does it cause abnormalities in lipid and glucose levels.

Bifeprunox recipients reported placebo levels of extrapyramidal adverse events, making it a prime candidate for the market. Phase III clinical trials are currently underway and a new drug application is due to be filed with the US Food and Drug Administration in 2006.

Double action Dainippon is conducting phase III trials of blonanserin (AD 5423, Lonansen), its promising potential schizophrenia drug. Blonanserin is a dual-action serotonin2 and dopamine D2 receptor antagonist that is structurally unrelated to existing antipsychotic agents on the market and is expected to be effective in the treatment of both positive and negative symptoms.

A phase III trial has shown the drug to deliver improvements on a Brief Psychiatric Rating Scale of 37.6 per cent total, and positive subscale and negative subscale scores of 24.6 per cent and 32.4 per cent, respectively, following 36 to 64 weeks of treatment.

The mean Drug-Induced Extrapyramidal Syndrome Scale score decreased from 1.6 at baseline to 0.3 after treatment. Patients experienced less frequent extrapyramidal symptoms with blonanserin compared with previous antipsychotic medications, and another phase III trial indicated an incidence of extrapyramidal symptoms of 53 per cent with blonanserin compared with 75 per cent in haloperidol-treated patients.

It is also expected that blonanserin will have minimal sedative and hypotensive effects, as it carries a weak potential for a1-adrenoceptor activation. Phase III clinical trials of tablet and powder formulations are ongoing in Japan. Improving compliance

US-based Johnson & Johnson is developing paliperidone (RO 76477, 9-hydroxy-risperidone), an active metabolite of risperidone, which was developed to improve patient compliance. It has an adverse event profile that is superior to the parent product.

Two formulations of paliperidone are in development, an oral paliperidone ER (extended-release) tablet which uses Alza Corporation's OROS controlled-release technology and a once-monthly injectable formulation that was generated using Elan's NanoCrystal technology. Phase III trials of both formulations in patients with schizophrenia are underway in the US.

Further treatment LU 31130 is another candidate from Lundbeck that is currently in phase I development for the treatment of psychosis. LU 31130 is an atypical treatment that has demonstrated antipsychotic activity and was associated with few adverse events in preclinical in vivo studies.

A phase I trial to establish its tolerability and pharmacokinetic profile has been initiated in Denmark and phase II development is expected to begin at the end of 2005.